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Potential Antitumor Agents VII. 5-Substituted 6-Phenylimidazo[21-b]thiazoles

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315182
Potential Antitumor Aaents
451
Arch. Pharm. (Weinheim) 315, 451-456 (1982)
Potential Antitumor Agents, VII
5 -Substituted 6-Phen ylimidazo[2,1-b]thiazoleso)
Aldo Andreani* , Daniela Bonazzi and Mirella Rambaldi
Istituto di Chimica Farmaceutica e Tossicologica, University of Bologna, Via Belmeloro 6,
40126Bologna (Italy)
Eingegangen am 19. Juni 1981
The Vilsmeier reaction for the synthesis of the 5-formylimidazo[2,l-b]thiazoles7-12 bearing a
p-substituted phenyl ring in position 6 is reported. These compoundswere used for the synthesisof the
thiosemicarbazones 7a-l2a, tosylhydrazones 7b-12b and 5-hydroxymethylderivatives 13-18 which,
in turn, were used as starting materials for preparing the methylcarbamic 13a-l8a, ethylcarbamic
13b-18b and acetic esters 13c-18c. Preliminary results in the P-388 leukemia test are reported.
Potentielle Antineoplastika, 7. Mitt.: 5-Substituierte 6-Phenylimidazo[2,1-b]thiazole
Die Vilsmeier-Reaktion zur Synthese der 5-Formylimidazo[2,1-b]thiazole
7-12 mit einer p-substituierten Phenylgruppe in 6-Stellung wird beschrieben. Diese Verbindungen dienten zur Herstellung der
Thiosemicarbazone 7a-12a, Tosylhydrazone 7b-12b und 5-Hydroxymethyl-Derivate 13-18, aus
denen die Methylcarbamidsaure- 13a-l8a, Ethylcarbamidsaure- 13b-18b und Essigsaure-Ester
13c-18c synthetisiert wurden. Die im P-388 Leukamie-Test ermittelten vorlaufigen Ergebnisse
werden angegeben.
Several papers from this laboratory have been devoted for some time to the search of new
antineoplastic agents, especially in the field of heterocyclic compounds’“’. This previous work
concerned the synthesis of hydrazone derivatives” and esters6’ of several 6-substituted imidazo[2,1-b]thiazoles and thiazolines. Beside the references already cited in these papers we want to
point out the most recent works in the field of hydrazone derivatives” and esters’) of heterocyclic
compounds as potential antitumor agents.
In this paper we report the synthesis and the antileukemic activity of thiosemicarbazones, tosylhydrazones and esters of imidazo [2,l-b] thiazoles and thiazolines bearing a
p-substituted phenyl ring in position 6.
Chemistry
The imidazo[2,1-b]thiazoles 1-3 and the corresponding 2,3-dihydro-derivatives 4-6
were prepared reacting 2-amino-thiazole or 2-amino-thiazoline with the proper bromo-acetophenone via previously described methods”’). The Vilsmeier reaction (see
”) Supported in part by the Italian National Research Council (CNR).
Presented in part at the XIV. National Congress of the Italian Chemical Society (Catania 21-25
Sept. 1981).
0365d233/82/05050451 $ 02.50/0
0 Verlag Chemie GmbH, Weinheim 1982
452
Arch. Pharm.
Andreani, Bonazzi and Rambaldi
Scheme 1)was then applied to the compounds 1-6.The resulting 5-formyl-derivatives 7-12
were used to prepare the hydrazone derivatives 7a-b l2a-b (see Table 1) and the
5-hydroxymethyl-derivatives 13-18 followed by the related esters 13a-c- 18a-c (see Table
1).
-
Tab. 1 : Thiosemicarbazones, Tosylhydrazones and Esters of 6-Substituted Imidazo [2,1 -bJ thiazoles.
Compound R
x
Solvent
Formula
gp
Calcd.
Found
C
H
N
7a
250*
EtOH
C13HloClNsS2
(335.8)
46.5
46.7
8a
243 -245d
EtOH
C14H13N5S2
(315.4)
53.3 4.15
53.5 4.42
22.2
22.0
9a
250*
DMFlHzO
C19H15N5S2
(377.5)
60.4 4.00
60.8 4.04
18.5
18.2
1Oa
233-235d
EtOH
CijH12ClN5S~
(337.9)
46.2
46.0
1 la
2 15- 220d
Et OH
C14H15NSSZ
(3 17.4)
53.0 4.76 22.1
53.0 5.00 22.0
129
268- 2 70d
DMF/H20
C19H17NSSZ
(379.5)
60.1 4.51
60.0 4.22
7b
125-130d
MeOH
C19H15ClN402Sz 52.9 3.51 13.0
(430.9)
52.6 3.75 12.9
8b
140-1 50d
MeOH
C Z O H ~ ~ N ~ 58.5
O ~ S 4.42
~
(410.5)
58.9 4.75
13.6
13.8
9b
135-140d
MeOH
CzsHzoN402Sz
(472.6)
11.9
11.6
lob
125-1354
MeOH
C19H17ClN402S2 52.7 3.96 12.9
(432.9)
52.5 4.02 12.8
1 lb
125-1354
MeOH
CzoH2oN402S2
(412.5)
3.00 20.9
2.97 20.6
3.58 20.7
3.45 20.6
63.5 4.27
63.3 4.21
18.4
18.3
58.2 4.88 13.6
58.1 5.05 13.2
315182
453
Potential Antitumor Agents
Tab. 1:Fortsetzung
CompoundR
x
cp
Solvent
Formula
CalCd.
Found
C
H
N
11.8
11.6
12b
140-150d
MeOH
63.3 4.67
63.1 4.85
13a
163-165d
Pt.Et.
52.2 3.76 13.1
52.2 3.98 13.0
14a
160-162d
CHClj
59.8 5.02 13.9
59.4 5.12 13.9
16a
140-142d
CHCls/Pt.Et.
51.9 4.35
51.6 4.52
17a
168-170d
CHClj /Pt.Et.
59.4 5.65 13.8
59.7 5.58 13.5
18a
199-203d
CHCl3
65.7 5.24 11.5
65.5 5.01 11.2
13b
140-145d
Pt.Et.
53.6 4.20
53.2 4.50
14b
131-133
Pt.Et.
.60.9 5.43 13.3
60.9 5.41 13.2
16b
158-161d
CHC13
53.3 4.77 12.4
53.6 4.70 12.1
l'7b
141-143
CHCl3/Pt.Et.
60.5 6.03 13.2
60.6 6.09 13.0
13c
128-130
R.Et.
54.8 3.61 9.13
54.8 3.61 9.05
14c
103-104
Pt.Et.
62.9 4.93 9.78
62.6 4.98 9.74
15c
168- 170
Pt.Et.
68.9 4.63 8.04
69.2 4.78 8.04
16c
117-120
CHCIs/Pt.Et.
54.4 4.24 9.07
54.6 4.22 8.84
17c
98-102
Pt.Et.
62.5 5.59 9.71
62.2 5.89 9.57
18c
175-177
CHC13/Pt.Et.
68.5 5.18 1.99
68.8 5.46 8.27
*
13.0
13.1
12.5
13.7
Approximative temperature at which the compound chars without melting.
Pharmacological Results
Thiosemicarbazones, tosylhydrazones and esters were tested in mice bearing P-388 leukemia,
accordingto the methods published by the National Cancer Institute, Bethesda, U.S.A.'2).The P-388
leukemia (lo6 cells) was inoculated intraperitoneally into each animal (day 0). The compounds were
454
Andreani, Bonazzi and Rambaldi
Arch. Pharm.
injected intraperitoneally at three different dose levels (day 1); median survival time was used as a
parameter. Results are expressed, for each dose, as T/C% i.e. the ratio of test (T) evaluation to
control (C) evaluation expressed as a percentage: a dose showing a T / C % 3 120 is considered active,
while a T/C%S 85 is considered toxic. Under these conditions the hydrazone derivatives resulted
inactive. Some esters demonstrated toxicity and will be tested at lower doses; the methylcarbamic
ester l3a and the ethylcarbamicester Wb gave a T/C% = 120 at 200 mg/Kg, while the acetic ester 17c
gave a T/C% = 133 at 50 mg/Kg. The activity of these compounds is still under investigation.
We are grateful to Mario Negri Institute (Milan) for evaluating the antitumor activity of our
compounds.
Experimental
Melting points are uncorrected. Bakerflex plates (Silica-gelIB2-F) were used for TLC. The IR spectra
were determined in Nujol with a Perkin-Elmer 177 spectrometer.
2,3-Dihydro-6-p-tolylimidazo[2,l-b]thiazole
(5)
10.6 g (50 mmol) of o-bromo-p-methyl-acetophenone was added to a solution of 5.1 g (50 mmol) 2amino-2-thiazolinein 60 ml of acetone and the reaction mixture was refluxed 2 h. After cooling the
precipitated salt was collected, washed with acetone, dried and treated with 200 ml of water and 50 ml
of 2N-HBr: after 1h reflux the solution was cooled and treated with 32 % NH,OH until alkaline. The
precipitate was collected and crystallized from ethanol: mp 146-148"C, yield 60 %. C,,HI2N,S (216.3)
Calcd.: C 66.6 H 5.59 N 13.0 Found: C 66.8 H 5.67 N 13.1 IR: 825, 745 cm-'.
General procedure for the formyl-derivatives 7-12
The Vilsmeier reagent was prepared by adding 7.7 g (50 mmol) of POCI, to a stirred and cooled
solution of 3.7 g (50 mmol) DMF in 5 ml CHCI,. To this reagent was added, in the same conditions, 10
mmol of the 6-substituted imidazo[2,1-b]thiazole1-6 dissolved in 30 ml CHCI, and 3 ml pyridine.
After 3 h at room temp. the reaction mixture was refluxed for 3-5 h (compounds 7-9) or 20-25 h
(compounds 10-12). The solvent was then evaporated under reduced pressure and the resulting oil
was poured onto ice. The precipitate was collected and crystallized with a yield of 60-80 %.
5-Formyl-6-p-chlorophenylimidazo
[2,1-b]thiazole
(7 R = C1 x = CH): mp 193-195°C (EtOH) C12H,CIN20S (262.7) Calcd.: C 54.9 H 2.68 N 10.7
Found: C 55.1 H 2.88 N 10.5 IR: 1640, 1260, 1090, 720 cm-'.
5-Formyl-6-p-tolylimidaz0[2,1
-b]thiazole
(8 R = CH, x = CH): mp 17&171"C (EtOH). Cl3Hl,N,OS (242.3) Calcd.: C 64.4 H 4.16 N 11.6
Found: C 64.1 H 4.05 N 11.5 IR: 1635, 1255, 1075, 725 cm-l.
5-Formyl-6-p-biphenytyEmidaz0[2,1 -b]thiazole
(9 R = C6H, x = CH): mp 165-166°C (EtOH) Cl8HI2N20S(304.4) Calcd.: C 71.0 H 3.97 N 9.2
Found: C 71.1 H 4.23 N 9.0 IR: 1625, 1250, 1090, 730 cm-'.
2,3-Dihydro-5-formyl-6-p-chlorophenylimidazo[2,1
-b]thiazole
(10 R = C1 x = CH,): mp 169-171°C (EtOH). Cl,H,CIN,OS (264.7) Calcd.: C 54.4 H 3.43 N 10.6
Found: C 54.5 H 3.45 N 10.5 IR: 1640, 1255, 1085, 830 cm-'.
315182
Potential Antitumor Agents
455
2,3-Dihydro-5-formyl-6-p-tolylimidazo[2,
I -b]thiazole
(11 R = CH, x = CH2): mp 164-167°C (EtOH). C13Hl,N20S (244.3) Calcd.: C 63.9 H 4.95 N 11.5
Found: C 63.6 H 4.69 N 11.3 IR: 1645, 1325, 1125, 830 cm-'.
2,3-Dihydro-5-formyl-6-p-biphenyIylimidazo[2,1
-b]thiazole
(12 R = C6Hs x = CH2): mp 173-175°C (EtOH). C18H14N20S(306.4) Calcd.: C 70.6 H 4.60 N 9.1
Found: C 70.8 H 4.71 N 9.2 IR: 1630, 1325, 770, 735 cm-'.
General procedure for the hydroxymethyl-derivatives 13-18
The formyl derivative (7-11: 10 mmol) was dissolved in methanol and treated under stirring and
cooling with small portions of NaBH, (90 mmol). After 3 h at room temp. the solution was refluxed for
2 h. The organic solvent was evaporated under reduced pressure and the hydroxymethyl-derivative
13-17 was separated by filtration or by extraction with chloroform in a yield of 70-90 %. Only
compound 18 was prepared reducing compound l2 with an equivalent of LiAIH, in anhydrous
THF.
5-Hydroxymethyl-6-p-chlorophenylimidazo[2,1
-b]thiazole
(13 R = C1 x = CH): mp 198-200°C (EtOH). C,,H,CIN,OS
Found C 54.2 H 3.41 N 10.4 IR: 3100,990 645 cm-'.
(264.7) Calcd.: C 54.4 H 3.43 N 10.6
5-Hydroxymethyl-6-p-tolylimidazo[2,
I -b]thiazole
(14 R = CH, x = CH): mp 188-190°C (EtOH). C13H12N20S(244.3) Calcd.: C 63.9 H 4.95 N 11.5
Found: C 63.6 H 4.95 N 11.2 JR: 3100, 990, 815, 770, 640 cm-'.
5-Hydroxymethyl-6-p-biphenylylimidazo[2,1
-b]thiazole
(15 R = C6H, x = CH): mp 220-222°C (DMF). CI8H,,N2OS (306.4) Calcd.: C 70.6 H 4.60 N 9.1
Found: C 70.7 H 4.85 N 9.3 IR: 3100, 990, 760, 690, 650 cm-'.
2,3-Dihydro-5-hydroxymethyl-6-p-chlorophenylimidazo[2,1
-b]thiazole
(16 R = C1 x = CH,): mp 215-220°C (MeOH). C,,HllCIN,OS (266.7)
Calcd.: C 54.0 H 4.16 N 10.5
'
Found: C 54.0 H 4,14 N 10.3 IR: 3130, 1480, 1000, 820 cm-'.
2,3-Dihydro-5-hydroxymethyl-6-p-tolylimidazo[2,
I -b]thiazole
(17 R = CH, x = CH,): mp 227-230°C (MeOH). C13H14N,0S(246.3) Calcd.: C 63.4 H 5.73 N 11.4
Found: C 63.7 H 5.60 N 11.4 IR: 3100, 1030, 1000, 820 cm-'.
2,3-~ihydro-5-hydroxymethyI-~-p-biphenylylimidazo[2,
I - b]thiazole
(18 R = C& X = CH2): mp 259-262°C (DMF). CigH&,OS (308.4) Calcd.: C 70.1 H 5.23 N 9.1
Found: C 70.5 H 5.44 N 9.3 IR: 3100, 1020, 840, 760, 720 cm-'.
General procedure for hydrazone derivatives and esters
A) The thiosemicarbazones 78-12s and the tosylhydrazones 7b-l2b were prepared refluxing an
ethanolic solution of the formyt-derivatives 7-12 with an equivalent of thiosemicarbazide or
tosylhydrazide in dil. ethanolic solution.
456
Andreani, Bonazzi and Rambaldi
Arch. Pharm.
B) Methylcarbamic (139-18a) and ethylcarbamic (13b-18b) esters were prepared treating 2 mmol of
the hydroxymethyl-derivatives 13-18 in THF with 60mmol CH,NCO or C,H,NCO and 5 mmol
triethylamine. The reaction mixture was refluxed 3-12 h (according to a TLC test), evaporated under
reduced pressure and crystallized.
C) The acetic esters 13cl8c were prepared treating 10 mmol of the hydroxymethyl-derivatives1 M 8
in 50mmol pyridine with 100mmol of acetic anhydride. After 2-3 h at room temp. the solution was
evaporated under reduced pressure and the residue was treated with water. The ester was isolated by
filtration or by extraction with chloroform and then crystallized.
Analytical pure hydrazone derivatives and esters are listed in Table 1.
References
1 A. Andreani, M. Rambaldi, D. Bonazzi, S . Filippeschi and C. Pintus, Boll. Chim. Farm. 116,370
(1977).
2 A. Andreani, D. Bonazzi, M. Rambaldi and G. Mungiovino, Boll. Chim. Farm. 118, 18
(1979).
3 A. Andreani, M. Rambaldi, D. Bonazzi, L. Greci and F. Andreani, Farmaco Ed. Sci. 34, 132
(1979).
4 A. Andreani, M. Rambaldi, D. Bonazzi, L. Greci and F. Andreani, Farmaco Ed. Sci. 34,1062
(1979).
5 A. Andreani, M. Rambaldi and D. Bonazzi, Farmaco Ed. Sci. 35, 573 (1980).
6 A. Andreani, D. Bonazzi and M. Rambaldi, Farmaco Ed. Sci. 35, 896 (1980).
7 Y. Mizuno, T. Endo, Y. Inoue, H. Tampo, A. Takahashi, M. Iigo, A. Hoshi and K. Kuretani,
Chem. Pharm. Bull. 28, 1584 (1980).
8 B.A. Teicher and A.C. Sartorelli, J. Med. Chem. 23,955 (1980); W.K. Anderson, J.S. New and
P.F. Corey, Arzneim. Forsch. 30, 765 (1980).
9 N.P. Buu-Hoi, N. Dat Xuong and T. Thu-CUC,Bull. SOC.Chim. Fr. 1966, 1277.
10 Y.V. Markova, K.K. Kuz’mina, E.M. Peresleni and M.N. Shchukina, Zh. Org. Khim. 1, 1475
(1965); C.A. 64, 2080 h (1966).
11 Metabio, Ger. Offen. 2,709,639 (15. Sept. 1977); C.A. 88, 22910r (1978).
12 R.I. Geran, N.H.Greenberg, M.M. Macdonald, A.M. Schumacher and B.J. Abbott, Cancer
Chemother. Rep. Part3, 3, 1 (1972).
[Ph 4521
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